Activation of cytotoxic and regulatory functions of NK cells by Sindbis viral vectors

• Published in: PloS one Vol. 6; no. 6; p. e20598
• Main Authors: Granot, Tomer, Venticinque, Lisa, Tseng, Jen-Chieh, Meruelo, Daniel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.06.2011; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Anticancer properties; B cells; Biology; Cancer; Cell activation; Cell Count; Cell Line, Tumor; Cell survival; Cell Transformation, Neoplastic - immunology; Combinatorial analysis; Cricetinae; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Female; Flow cytometry; Genes, MHC Class II - genetics; Genetic Vectors - genetics; Genetic Vectors - immunology; Health aspects; Humans; Immune system; Interferon-gamma - metabolism; Interleukin; Interleukin 1; Interleukin 12; Interleukin-12 - genetics; Killer cells; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - transplantation; Lac Operon - genetics; Macrophages; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Natural killer cells; Oncolysis; Oncolytic viral therapy; Oncolytic Virotherapy; Ovarian cancer; Ovarian carcinoma; Peritoneum; Peritoneum - immunology; Peritoneum - metabolism; Rodents; Sindbis Virus - genetics; Sindbis Virus - immunology; Sindbis Virus - physiology; T cell receptors; Therapy; Toxicity; Tumors; Up-Regulation - immunology; Vectors (Biology); Viruses; Xenografts; Xenotransplantation; γ-Interferon; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020598

Oncolytic viruses (OVs) represent a relatively novel anti-cancer modality. Like other new cancer treatments, effective OV therapy will likely require combination with conventional treatments. In order to design combinatorial treatments that work well together, a greater scrutiny of the mechanisms behind the individual treatments is needed. Sindbis virus (SV) based vectors have previously been shown to target and kill tumors in xenograft, syngeneic, and spontaneous mouse models. However, the effect of SV treatment on the immune system has not yet been studied. Here we used a variety of methods, including FACS analysis, cytotoxicity assays, cell depletion, imaging of tumor growth, cytokine blockade, and survival experiments, to study how SV therapy affects Natural Killer (NK) cell function in SCID mice bearing human ovarian carcinoma tumors. Surprisingly, we found that SV anti-cancer efficacy is largely NK cell-dependent. Furthermore, the enhanced therapeutic effect previously observed from Sin/IL12 vectors, which carry the gene for interleukin 12, is also NK cell dependent, but works through a separate IFNγ-dependent mechanism, which also induces the activation of peritoneal macrophages. These results demonstrate the multimodular nature of SV therapy, and open up new possibilities for potential synergistic or additive combinatorial therapies with other treatments.